Stapled Peptides with γ‐Methylated Hydrocarbon Chains for the Estrogen Receptor/Coactivator Interaction. Issue 13 (1st March 2016)

• Record Type: Journal Article
• Authors: Speltz, Thomas E.; Fanning, Sean W.; Mayne, Christopher G.; Fowler, Colin; Tajkhorshid, Emad; Greene, Geoffrey L.; Moore, Terry W.
• Is Part Of: Angewandte Chemie international edition. Volume 55:Issue 13(2016)
• Page Start: 4252
• Page End: 4255
• Publication Date: 2016-03-01
• Subjects: amino acids -- conformational analysis -- peptides -- peptidomimetics -- receptors; Chemistry -- Periodicals; 540
• DOI: 10.1002/anie.201510557
• Languages: English
• ISSNs: 1433-7851

Abstract

Abstract: "Stapled" peptides are typically designed to replace two non‐interacting residues with a constraining, olefinic staple. To mimic interacting leucine and isoleucine residues, we have created new amino acids that incorporate a methyl group in the γ‐position of the stapling amino acid S5. We have incorporated them into a sequence derived from steroid receptor coactivator 2, which interacts with estrogen receptor α. The best peptide (IC50 =89 nm ) replaces isoleucine 689 with an S ‐γ‐methyl stapled amino acid, and has significantly higher affinity than unsubstituted peptides (390 and 760 nm ). Through X‐ray crystallography and molecular dynamics studies, we show that the conformation taken up by the S ‐γ‐methyl peptide minimizes the syn ‐pentane interactions between the α‐ and γ‐methyl groups. Abstract : Branching out : γ‐Branched stapling amino acids were synthesized and incorporated into peptides to produce high‐affinity inhibitors of the estrogen receptor/steroid receptor coactivator interaction. Some branched stapled peptides were more effective than the unfunctionalized peptide. The influence of 1, 5‐interactions on peptide conformation was analyzed by circular dichroism, X‐ray crystallography, and molecular dynamics.